Background:Long-QT syndrome (LQTS) is characterized by a prolonged heart rate–corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ≈8% to 10% of QTc variation in the general population.Methods:Overall, 423 patients with LQT1, LQT2, or LQT3 were genotyped for 61 QTc-associated genetic variants used in a prototype QTc–polygenic risk score (QTc-PRS). A weighted QTc-PRS (range, 0–154.8 ms) was calculated for each patient, and the FHS (Framingham Heart Study) population-based reference cohort (n=853).Results:The average QTc-PRS in LQTS was 88.0±7.2 and explained only ≈2.0% of the QTc variability. The QTc-PRS in LQTS probands (n=137; 89.3±6.8) was significantly greater than both FHS controls (87.2±7.4, difference-in-means±SE: 2.1±0.7, P<0.002) and LQTS genotype-positive family members (87.5±7.4, difference-in-mean, 1.8±.7, P<0.009). There was no difference in QTc-PRS between symptomatic (n=156, 88.6±7.3) and asymptomatic patients (n=267; 87.7±7.2, difference-in-mean, 0.9±0.7, P=0.15). LQTS patients with a QTc≥480 ms (n=120) had a significantly higher QTc-PRS (89.3±6.7) than patients with a QTc<480 ms (n=303, 87.6±7.4, difference-in-mean, 1.7±0.8, P<0.05). There was no difference in QTc-PRS or QTc between genotypes.Conclusions:The QTc-PRS explained <2% of the QTc variability in our LQT1, LQT2, and LQT3 cohort, contributing 5× less to their QTc value than in the general population. This prototype QTc-PRS does not distinguish/predict the clinical outcomes of individuals with LQTS.

中文翻译：

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校正 QT 间期多基因风险评分及其对先证者和基因型阳性家庭成员 1 型、2 型和 3 型长 QT 综合征的影响。

背景：长 QT 综合征 (LQTS) 的特征是延长的心率校正 QT 间期 (QTc)。全基因组关联研究确定了共同解释一般人群中约 8% 至 10% QTc 变异的常见遗传变异。原型 QTc-多基因风险评分 (QTc-PRS)。计算每位患者的加权 QTc-PRS（范围，0-154.8 ms），并计算 FHS（弗雷明汉心脏研究）基于人群的参考队列（n=853）。结果：LQTS 中的平均 QTc-PRS 为 88.0± 7.2 并仅解释了 QTc 变异性的 ≈2.0%。LQTS 先证者（n=137；89.3±6.8）的 QTc-PRS 显着高于两个 FHS 对照（87.2±7.4，均值差异±SE：2.1±0.7，P<0.002) 和 LQTS 基因型阳性家族成员 (87.5±7.4，均值差异，1.8±.7，P <0.009)。有症状（n=156，88.6±7.3）和无症状患者（n=267；87.7±7.2，均值差异，0.9±0.7，P=0.15）的 QTc-PRS 没有差异。QTc≥480 ms 的 LQTS 患者 (n=120) 的 QTc-PRS (89.3±6.7) 显着高于 QTc<480 ms 的患者 (n=303, 87.6±7.4, 均值差异, 1.7± 0.8，P < 0.05）。基因型之间的 QTc-PRS 或 QTc 没有差异。 结论：在我们的 LQT1、LQT2 和 LQT3 队列中，QTc-PRS 解释了 <2% 的 QTc 变异，对其 QTc 值的贡献比一般人群少 5 倍. 该原型 QTc-PRS 不区分/预测 LQTS 个体的临床结果。